Project Summary/Abstract The long-term goal of these studies is to advance high-density diffuse optical tomography (HD-DOT) methods for evaluating brain-behavior relationships in infants and toddlers at risk for developing autism spectrum disorder (ASD) while they are awake and engaged within a naturalistic setting. This application is being submitted in response to FOA: RFA-MH-18-200, NIMH Biobehavioral Research Awards for Innovative New Scientists (BRAINS R01), because the PI is an early stage investigator who is building a program of research that is highly innovative, transformative, and has the potential to elucidate underlying mechanisms, inform clinical interventions, and improve outcome of ASD. As such, this research is harmonious with the mission of NIMH: to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. ASD, defined by deficits in social communication and restricted interests/repetitive behaviors, is a serious psychiatric disorder of childhood, is treatable but currently incurable, and affects an estimated 1 in 59 children in the United States at an estimated annual cost of $268B. Early behavioral and educational interventions, starting at 18-24 months of age, improve outcomes in a subset of patients. Neuroimaging methods, including both task-based functional magnetic resonance imaging (fMRI) and task-free functional connectivity MRI, have demonstrated sensitivity to neural signatures of ASD that may inform diagnosis and track responses to interventions. However, the MRI environment can prove intolerable for many children due to noise, claustrophobia, and the need to lie supine and still. HD-DOT provides a compelling alternative that overcomes the significant ergonomic limitations of fMRI and silently images brain function with a wearable cap in a naturalistic setting ideal for studies on awake and engaged infants and toddlers. However, studies in young children over multiple imaging sessions present significant challenges in optical data registration and fidelity that motivate a new set of software tools to enable accurate and reliable mapping of brain function. Here we address these needs by developing novel algorithms for photometric head modeling and data fidelity management. With these advancements, we will conduct a prospective longitudinal study of brain function and behavior in toddlers at risk for developing ASD. Specifically, we will measure neural signatures derived from naturalistic movie viewing, determine the relationship between these signatures and behavioral assays across development, and investigate how these signatures are affected in toddlers at risk for ASD in a case-control sample. These data may provide markers to the specific aspects of impaired behavior observed in ASD, namely affected social communication, receptive and expressive language, motor coordination disruption, and even restricted and repetitive behaviors. Further, this strategy provides a diversified approach to assessment that will be applicable across development, and may facilitate identification of common mechanisms by which disparate genetic pathways to autism result in the broad autistic phenotype.